Alzheimer’s disease associated genes ankyrin and tau cause shortened lifespan and memory loss in Drosophila
dc.contributor.author | Higham, JP | |
dc.contributor.author | Malik, BR | |
dc.contributor.author | Buhl, E | |
dc.contributor.author | Dawson, JM | |
dc.contributor.author | Ogier, AS | |
dc.contributor.author | Lunnon, K | |
dc.contributor.author | Hodge, JJL | |
dc.date.accessioned | 2020-01-09T09:42:29Z | |
dc.date.issued | 2019-06-11 | |
dc.description.abstract | Alzheimer’s disease (AD) is the most common form of dementia and is characterized by intracellular neurofibrillary tangles of hyperphosphorylated Tau, including the 0N4R isoform and accumulation of extracellular amyloid beta (Aβ) plaques. However, less than 5% of AD cases are familial, with many additional risk factors contributing to AD including aging, lifestyle, the environment and epigenetics. Recent epigenome-wide association studies (EWAS) of AD have identified a number of loci that are differentially methylated in the AD cortex. Indeed, hypermethylation and reduced expression of the Ankyrin 1 (ANK1) gene in AD has been reported in the cortex in numerous different post-mortem brain cohorts. Little is known about the normal function of ANK1 in the healthy brain, nor the role it may play in AD. We have generated Drosophila models to allow us to functionally characterize Drosophila Ank2, the ortholog of human ANK1 and to determine its interaction with human Tau and Aβ. We show expression of human Tau 0N4R or the oligomerizing Aβ 42 amino acid peptide caused shortened lifespan, degeneration, disrupted movement, memory loss, and decreased excitability of memory neurons with co-expression tending to make the pathology worse. We find that Drosophila with reduced neuronal Ank2 expression have shortened lifespan, reduced locomotion, reduced memory and reduced neuronal excitability similar to flies overexpressing either human Tau 0N4R or Aβ42. Therefore, we show that the mis-expression of Ank2 can drive disease relevant processes and phenocopy some features of AD. Therefore, we propose targeting human ANK1 may have therapeutic potential. This represents the first study to characterize an AD-relevant gene nominated from EWAS. | en_GB |
dc.description.sponsorship | GW4 accelerator award | en_GB |
dc.description.sponsorship | Alzheimer's Society | en_GB |
dc.description.sponsorship | Leverhulme Trust | en_GB |
dc.identifier.citation | Vol. 13, article 260 | en_GB |
dc.identifier.doi | 10.3389/fncel.2019.00260 | |
dc.identifier.grantnumber | GW4-AF2-002 | en_GB |
dc.identifier.grantnumber | RPG-2016-31 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/40309 | |
dc.language.iso | en | en_GB |
dc.publisher | Frontiers Media | en_GB |
dc.rights | © 2019 Higham, Malik, Buhl, Dawson, Ogier, Lunnon and Hodge. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | en_GB |
dc.subject | Alzheimer’s disease | en_GB |
dc.subject | Drosophila | en_GB |
dc.subject | memory | en_GB |
dc.subject | lifespan | en_GB |
dc.subject | locomotion | en_GB |
dc.subject | neurodegeneration | en_GB |
dc.subject | Tau | en_GB |
dc.subject | Ankyrin | en_GB |
dc.title | Alzheimer’s disease associated genes ankyrin and tau cause shortened lifespan and memory loss in Drosophila | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2020-01-09T09:42:29Z | |
dc.identifier.issn | 1662-5102 | |
dc.description | This is the final version. Available on open access from Frontiers Media via the DOI in this record | en_GB |
dc.identifier.journal | Frontiers in Cellular Neuroscience | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2019-05-23 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2019-06-11 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2020-01-09T09:39:58Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2020-01-09T09:42:35Z | |
refterms.panel | A | en_GB |
refterms.depositException | publishedGoldOA |
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Except where otherwise noted, this item's licence is described as © 2019 Higham, Malik, Buhl, Dawson, Ogier, Lunnon and Hodge. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.